Modifying chemoselectivity during oxidation of nitrogen compounds

ABSTRACT

The invent concerns a method for chemoselective oxidation of an organic compound comprising several potentially oxidizable groups whereof at least one is a nitrogen group. Said method is characterised in that it consists in using at least a protic solvent, which is a good donor of hydrogen bonds, enabling to limit N-oxidation.

PRIOR ART

[0001] Metabolic studies are an important part of drug development andmake it possible to predict the metabolites that will be obtained uponconversion of a given compound by body enzymes. P450 cytochromes, themain enzymes involved in the bioconversion of drugs, catalyze oxidationreactions. From an economic point of view, it is of great interest totry to predict, in vitro, the metabolites which will result from thebioconversion of a compound. For example, many drugs containnitrogen-containing groups which may be metabolized to N-oxidizedderivatives by these monooxygenase enzymes. In general, these N-oxidizedproducts can readily be synthesized by conventional oxidation methods(e.g., reaction with peracids). In contrast to N-oxidized products,other oxidation products such as products of hydroxylation are difficultto synthesize from the starting material.

[0002] Use of metalloporphyrines to catalyze the oxidation of organiccompounds, as described in patent application PCT 96/08455, makes itpossible to mimic the oxidation reactions which take place in biologicalsystems, and to prepare the potential metabolites resulting, among otherthings, from the N-oxidation and hydroxylation of the starting material.However, because of their nonbinding doublet, nitrogen-containing groupsare rich in electrons and hence are generally more reactive underoxidation conditions than are carbon-hydrogen bonds.

[0003] During oxidation reactions one can obtain satisfactory results ofhydroxylation of the starting material by using a salt of the startingmaterial or by carrying out the reaction in a strongly acid medium (byadding to the reaction medium strong Brönsted acids such as hydrochloricor trifluoroacetic acid). The presence of these strong Brönsted acidsbrings about complete protonation of the nitrogen-containing groups ofthe organic compound to be oxidized. Nevertheless the salts ofcorresponding nitrogen-containing compounds are not always stable in thereaction medium, and/or the presence of a strong Brönsted acid in themedium can be harmful to the starting material and/or to the oxidationproducts.

SUMMARY OF THE INVENTION

[0004] The invention makes it possible to solve this technical problemby employing a process carried out under mild conditions and using aprotic solvent or co-solvent whose properties permit orienting thechemoselectivity of the oxidation reaction.

[0005] In particular, the invention makes it possible to avoid theinstability problems which may result from the use of salts of thecompound to be oxidized, and also to avoid racemization and/ordegradation of the starting materials and/or of the oxidation productsand/or of the reagents, drawbacks which characterize the use of strongacids.

[0006] Hence the present invention relates to a process ofchemoselective oxidation of an organic compound having severaloxidizable groups, at least one of which is a nitrogen-containing group.The process consists in contacting an organic compound to be oxidizedwith a reaction mixture comprising an oxidizing agent in a proticsolvent which is a good donor of hydrogen bonds, and is optionallyaccompanied by an inert aprotic solvent. The protic solvent is capableof forming a hydrogen bond with a nitrogen-containing group of thecompound to be oxidized, thus limiting the oxidation of thisnitrogen-containing group, thereby favoring the oxidation of otherfunctional groups of the compound to be oxidized. The process thenconsists in recovering the products resulting from the oxidationreaction.

[0007] The present invention also relates to a process of chemoselectiveoxidation of an organic compound having several oxidizable groups, atleast one of which is a nitrogen-containing group. The process consistsin contacting said organic compound with a reaction mixture comprisingan oxidizing agent and a protic solvent. The protic solvent is capable,in said reaction medium, of forming a hydrogen bond with one or severalnitrogen-containing groups of said organic compound, without leading tocomplete protonation of said nitrogen-containing group or groups,thereby favoring the oxidation of other functional groups of thecompound to be oxidized. The process then consists in recovering theproducts resulting from the oxidation reaction.

[0008] The process of the invention may be used in metabolic studies. Ineffect it makes it possible to change the proportion of the differentproducts obtained at the end of the oxidation of an organic compoundwhose potential metabolites the researchers wish to know, and inparticular, to increase the yield of oxidation products that aredifficult to obtain under conventional oxidation conditions. It may alsopermit to obtain supplementary metabolites and thus change the nature ofthe products obtained at the end of the oxidation reaction.

[0009] The invention is described in greater detail in the followingdescription as well as in FIG. 1 which shows the effect of differentsolvents or solvent mixtures on the nature and proportion of theproducts obtained at the end of the oxidation ofN-(9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)isonicotinamide(1) in the presence of an oxidizing agent (iodosobenzene) and a catalyst(manganese (tetra-(2,6-dichlorophenyl)porphyrin).

DETAILED DESCRIPTION OF THE INVENTION

[0010] When an organic compound having several oxidizable groups is in areaction medium corresponding to oxidation conditions, the differentpotentially oxidizable sites of said compound are in competitionvis-a-vis the oxidizing agent. In that case it is the site most reactiveunder oxidation conditions that is mainly oxidized.

[0011] Because of their nonbinding electron doublet, nitrogen-containingcompounds or groups are generally very reactive under oxidationconditions, because the latter involve electrophilic reagents. Thus whena nitrogen-containing organic compound is used as reagent in anoxidation reaction, the majority products obtained will originate fromthe nitrogen-containing group.

[0012] Hence the consequence of the process of the invention is to limitthe oxidation of one or several nitrogen-containing groups present inthe organic compound, in favor of other, less reactive functional groupspresent in the same organic compound.

[0013] Preferentially, the process of the invention makes it possible toobtain a proportion of N-oxidized products with respect to the totalamount of products resulting from the reaction, of between 0 and 50%.More particularly, the process of the invention makes it possible toobtain a proportion of N-oxidized products with respect to the totalamount of products resulting from the reaction, of between 0 and 20%, 0and 15%, or 0 and 5%.

[0014] The present process comprises the use of an oxidizing agent andof a protic solvent that is a good donor of hydrogen bonds, and ischaracterized by a high α parameter. Parameters α and β make itpossible, respectively, to measure the ability of a molecule to donate ahydrogen bond and the ability of a molecule to accept a hydrogen bond(for more details, see: Michael H. Abraham, Chem. Dep., Univ. Coll.London, London, UK. Chem. Soc. Rev. (1993), 22(2), 73-83). Such asolvent, having a high α parameter, may form a complex, within thestarting material, with the functional group having the highest,parameter, that is one being the best hydrogen bond acceptor. A hydrogenbond is thus formed between the nitrogen-containing group or groupswhose oxidation is to be limited (this type of group generally has ahigh β parameter) and the protic solvent used. Formation of this bondgreatly decreases the reactivity of nitrogen toward the oxidizing agentand permits the oxidation of other functional groups. Thus the proticsolvent is selected so that the formation of hydrogen bonds between ahydrogen of the solvent (hydrogen bond donor) and nonbinding doublet ofthe nitrogen (hydrogen bond acceptor) of the nitrogen-containing groupof the organic compound do not lead to complete protonation of saidnitrogen-containing group.

[0015] Understood by the term “complete protonation of anitrogen-containing group” is the fact that there is only a negligibleamount of non-protonated nitrogen-containing group in the reactionmedium.

[0016] Thus, as mentioned above, the process of the invention makes itpossible to orient the chemoselectivity of the reaction, which allowslimitation of the N-oxidation of the nitrogen-containing groups presentin the starting material and which thus promotes the oxidation of otherfunctional groups of the compound to be oxidized, such as thecarbon-hydrogen bonds or carbon-carbon double bonds.

[0017] This type of chemoselectivity may be called N-chemoselectivity.

[0018] The process of the invention makes it possible, for example, topromote the hydroxylation of carbon-hydrogen bonds of an organiccompound having one or more nitrogen-containing groups.

[0019] The terms “nitrogen-containing group” or “nitrogen-containingcompound” are used here to designate any functional group containing anitrogen, and, more particularly, amines (primary, secondary andtertiary), amides, imines, nitrites and optionally substituted aromaticor nonaromatic heterocycles which contain at least one nitrogen atom.The organic compound to be oxidized contains one or morenitrogen-containing groups selected from the functional groups listedabove. Preferably, the organic compound to be oxidized contains onenitrogen-containing group selected from the functional groups listedabove.

[0020] The oxidation reaction according to the process of the inventionmay be carried out in the presence of a catalyst, particularly in thepresence of a metalloporphyrin, a compound which makes it possible tomimic the bioconversions undergone by a drug in a biological system.

[0021] Thus, the presence of the protic compound or solvent which is agood hydrogen bond donor and very weak Brönsted acid makes it possibleto vary the chemoselectivity of the oxidation reaction under conditionsthat are milder than those using a strong Brönsted acid or an acidhaving a pK_(a) of less than 7.

[0022] In certain cases when the pK_(a) of the protic solvent is lowerthan that of the conjugated acid of the oxidizable nitrogen-containingcompound, the formation of a hydrogen bond between a nitrogen-containinggroup of the compound to be oxidized and the protic solvent may lead toprotonation of the nitrogen. This protonation or ionization of thenitrogen is preferably a partial one.

[0023] Understood by the term “partial protonation” is a proportion oforganic compound to be oxidized whose nitrogen-containing group orgroups are protonated by the the protic solvent to an extent of lessthan 80%, 50%, 20%, 10% or 1% with respect to the same nonprotonatedcompound.

[0024] Protic Solvent or Co-Solvent

[0025] The protic solvent used in the process of the invention iscapable, in the reaction medium, of forming a hydrogen bond with one ormore nitrogen-containing groups of the organic compound to be oxidized,without leading to complete protonation of said nitrogen-containinggroup or groups.

[0026] More particularly, the protic solvent used in the process of theinvention is a protic solvent that is a very weak Brönsted acid capable,in the reaction medium, of forming a hydrogen bond with one or morenitrogen-containing groups of the organic compound to be oxidized.

[0027] The term “protic solvent that is a very weak Brönsted acid” ispreferably understood to designate a solvent characterized by a pK_(a)equal to or greater than 9.

[0028] The term “protic solvent capable of forming a hydrogen bond” isunderstood to mean a solvent that is a good donor of hydrogen bonds.This solvent that is a good hydrogen-bond donor is advantageouslycharacterized by a high α parameter.

[0029] Preferably, a high α parameter will be greater than 0.43. In aparticularly preferred manner, a high α parameter will be equal to orgreater than 0.55.

[0030] Advantageously, the protic solvent is, in addition, highly polarand/or weakly nucleophilic.

[0031] The preferred solvent is highly polar and weakly nucleophilic.

[0032] This solvent should be protic, very weakly acidic in the sense ofBrönsted (pK_(a)≧9) and have a high α parameter, i.e., be a goodhydrogen bond donor.

[0033] The following examples illustrate but do not limit the choice ofprotic solvent. The protic solvent may be an alcohol such as isopropanolor tert.-butyl alcohol (or 2-methylpropanol-2).

[0034] The solvent is preferably a fluorinated alcohol such as2-fluoroethanol, 2,2,2-trifluoroethanol,1,1,1,3,3,4,4,4,-octafluorobutanol-2,2,2,3,3,4,4,4-heptafluorobutanol-1,2,2,3,3,3-pentafluoropropanol-1,1,1,1,3,3,3-hexafluoro-2-methylpropanol-2,or 1,1,1,3,3,3,-hexafluoropropanol-2 (or hexafluoroisopropanol). Thepreferred protic solvent is hexafluoroisopropanol, because it is anextremely powerful hydrogen-bond donor (very high α parameter) and avery weak hydrogen-bond acceptor. Moreover, this compound is readilyeliminated at the end of reaction by evaporation under reduced pressure,since it is highly volatile (boiling point 59° C.).

[0035] The protic compound of the process of the invention can be usedas the sole solvent or as co-solvent in the reaction medium.

[0036] When the protic compound is used as co-solvent, the reactionmedium contains another solvent, the main inert and aprotic solvent,which reacts neither with the reactants nor with the reaction products.In that case the protic compound, thanks to its properties, also has theadvantage of facilitating dissolution of the product to be oxidized inthe main solvent.

[0037] The amount of protic co-solvent used generally represents 1 to30% equivalent by volume with respect to the main solvent. Preferably,10% are used.

[0038] When the protic compound which allows the selectivity of thereaction to be varied is used as the sole solvent without main solvent,it permits, in that case, both the dissolution of the reactants and thechemoselectivity of the oxidation reaction.

[0039] The total amount of solvent is calculated so as to obtain asolution whose concentration of starting material is between 0.05 M and0.5 M. The concentration of starting material is preferably 0.1 M. Thetotal amount of solvent comprises the main solvent and the proticco-solvent if the protic compound is used as co-solvent, or the proticsolvent alone if the protic compound is used as the sole solvent.

[0040] The use of the protic compound as the sole solvent or co-solvent,and the amount and nature of the protic compound to be used areparameters which a person skilled in the art can easily determine byroutine experimentation.

[0041] Main Solvent

[0042] When the protic compound is used as co-solvent in the reactionmedium, the main solvent is so selected that it reacts neither with thestarting material nor with the reaction products. An inert aproticsolvent is preferred which does not interfere with the oxidationreaction. This main solvent can itself be composed of a combination ofseveral solvents.

[0043] The following examples illustrate but do not limit the choice ofmain solvent. The main solvent may be a polyhalogenated aliphaticsolvent such as 1,1,2-trichloro-1,2,2-trifluoroethane ordichloromethane, a polyhalogenated organic solvent such as1,2-dichlorobenzene, 1,2,4-trichlorobenzene, pentafluorobenzene ortrifluorotoluene. Trifluorotoluene is the preferred main solvent,because it can dissolve many different organic compounds while having alow reactivity under the oxidation conditions.

[0044] Oxidizing Agent

[0045] Numerous oxidizing agents may be used in the process of theinvention. In effect the nature of the oxidizing agent is not a limitingfactor in the course of an oxidation reaction according to the processof the invention. Persons skilled in the art can select the appropriateoxidizing agent from the wide variety of available oxidizing agents.

[0046] The following examples illustrate but do not limit the choice ofoxidizing agent. The most frequently used oxidizing agents includem-chloroperbenzoic acid, magnesium monoperoxyphthalate,dimethyldioxirane and potassium monopersulfate.

[0047] If a catalyst such as a metalloporphyrin is used in the processof the invention, the oxidizing agent many be iodosobenzene, a 30 to 45%aqueous solution of hydrogen peroxide, an anhydrous source of hydrogenperoxide such as sodium percarbonate, urea-hydrogen peroxide complex orthe like, potassium monopersulfate, sodium hypochlorite, tert.-butylhydroperoxide, cumene hydroperoxide, m-chloroperbenzoic acid, ormagnesium monoperoxyphthalate. Preferred oxidizing agents includeiodosobenzene, any source of hydrogen peroxide, or potassiummonopersulfate.

[0048] Hydrogen peroxide is more effective in the presence of aco-catalyst such as imidazole, ammonium acetate, N-hexylimidazole, amineN-oxides, tetrabutylammonium acetate, tert.-butylpyridine, pyridine,4-methylpyridine, and 2,4,6-trimethylpyridine. The oxidizing agentscited in the following reference may also be used in the process of theinvention: “State of the art in the development of biomimetic oxidationcatalysts” by A. M. A Rocha Gonsalves and M. M. Pereira, J. Mol. Catal.A: Chem. 1996, 113, 209.

[0049] Metalloporphyrins

[0050] Synthetic metalloporphyrins are described in the internationalpatent application WO 96/08455. The term “metalloporphyrin” used aboverefers to porphyrins of formula (I):

[0051] wherein

[0052] R1, R2 and R3 each independently represents a hydrogen atom or anelectronegative group such as Cl, F, Br, SO3Na or an equivalent group,

[0053] R4, R5; R6, R7, R8, R9, R10 and R11 each independently representsa hydrogen atom or an electronegative group such as Cl, F, Br, SO3Na oran equivalent group,

[0054] R12 is Cl, acetate or an equivalent group,

[0055] M is selected from the group consisting of iron, manganese,chromium, ruthenium, cobalt, copper and nickel.

[0056] Preferred metalloporphyrins include manganese (III)tetra(pentafluorophenyl)porphyrin, abbreviated herein as Mn(TPFPP)Cl,which is the compound of formula (I) above wherein M is manganese, R1,R2 and R3 are fluorine, R4, R5, R6, R7, R8, R9, R10 and R11 arehydrogen, and R12 is chlorine.

[0057] Preferred metalloporphyrins also include:

[0058] iron tetra(pentafluorophenyl)porphyrin, abbreviated herein asFe(TPFPP)Cl, which is the compound of formula (I) above wherein M isiron, R1, R2 and R3 are fluorine, R4, R5, R6, R7, R8, R9, R10 and R11are hydrogen and R12 is chlorine;

[0059] manganese tetra-(2,6-dichlorophenyl)porphyrin, abbreviated hereinas Mn(TDCPP)Cl, which is the compound of formula (I) above wherein M ismanganese, R1 is chlorine, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11are hydrogen and R12 is chlorine;

[0060] iron tetra-(2,6-dichlorophenyl)porphyrin, abbreviated herein asFe(TDCPP)Cl, which is the compound of formula (I) above wherein M isiron, R1 is chlorine, R2, R3, R4, R5, R6, R7, R8, R9, R10 and R11 arehydrogen and R12 is chlorine;

[0061] iron tetra-(2,6-dichlorophenyl)-octachloroporphyrin, abbreviatedherein as Fe(TDCPCl₈P)Cl, which is the compound of formula (I) abovewherein M is iron, R1 is chlorine, R2 and R3 are hydrogen, R4, R5, R6,R7, R8, R9, R10 and R 11 are chlorine and R12 is chlorine;

[0062] the compound Mn((Cl₂Ph)₄(NO₂)P)Cl, which is the compound offormula (I) above wherein M is manganese, R1 is chlorine, R4 is NO₂, R2,R3, R5, R6, R7, R8, R9, R10 and R11 are hydrogen and R12 is chlorine;

[0063] the compound Mn((Cl₂Ph)₄(NO₂)₂P)Cl, which is the compound offormula (I) above wherein M is manganese, R1 is chlorine, R5 and R6 areNO₂, R2, R3, R4, R7, R8, R9, R10 and R11 are hydrogen and R12 ischlorine.

[0064] The amount of metalloporphyrin used ranges from 0.5 to 10% molarand is preferably 1% molar with respect to the starting material.

[0065] Temperature and Duration of the Reaction

[0066] The temperature of the reaction is between −20° C. and 100° C.,and preferably between −10° C. and 40° C.

[0067] The duration of the reaction varies between a few minutes and 2hours. Progress of the reaction can be monitored by analyticaltechniques such as thin-layer chromatography or HPLC. The reaction isstopped when the oxidation reaction reaches a plateau point beyond whichno further conversion of the starting material is observed.

[0068] Experimental Part

[0069] Without limiting the invention, the following examples illustratethe implementation of the process of the invention.

[0070] The purity is verified by high-performance liquid chromatography(HPLC) on a Merck Lachrom instrument, and the retention time observed isreported for the eluent used.

[0071] The identity of the products obtained with the proposedstructures is verified by their proton nuclear magnetic resonance and bymass spectrography.

[0072] The ¹H NMR spectra are recorded at 400 MHz on a Brükerinstrument, the compounds being dissolved in deuterochloroform, withtetramethylsilane as internal standard. The nature of the signals, theirchemical shifts in ppm and the number of protons they represent arenoted.

[0073] The mass spectra are recorded on a Micromass Platform LCspectrometer with positive electrospray.

EXAMPLE 1

[0074] Oxidation ofN-(9-methyl-4-oxo-1-phenyl-3,4,6,7-tetrahydro-[1,4]diazepino[6,7,1-hi]indol-3-yl)-isonicotinamide(1) With 1 Equivalent of Iodosobenzene (PhIO) Catalyzed by Manganesetetra-(2,6-dichlorophenyl)porphyrin Mn(TDCPP)Cl in Various Solvents

[0075] These reactions in the presence of a single equivalent ofiodosobenzene yield oxidation products 2, 3, 4, 5, 6 and 7 in additionto unconverted starting material, as illustrated by Scheme 1:

[0076] Compound 1 (39.6 mg, 100 μmol) is dissolved in the solventmixture chosen (960 μL) by adding, if necessary, first the proticsolvent (here used as co-solvent) and then the main solvent(dichloromethane or trifluorotoluene). The solution is stirred for 30minutes before adding a solution of 25 mM of manganesetetra-(2,6-dichlorophenyl)porphyrin MN(TDCPP)Cl in dichloromethane (40μL, 1 μmol, 1 mol %). After 15 minutes iodosobenzene PhIO (22 mg, 1equiv.) is added. One hour after the addition the reaction is monitoredby analytical HPLC of a sample consisting of 10 μL of reaction mixture,10 μL of a solution of 10 mM internal standard in 1:1methanol/acetonitrile and 980 μL of a 1:1 solution of methanol andacetonitrile. The structure of the internal standard is as follows:

[0077] The sample is injected into a Kromasil 5C18 250×4.6 mm column andeluted at 1 mL/min with a gradient of acetonitrile and methanol in water(furnace temperature 25° C., UV 240 nm): min % MeOH % CH₃CN % H₂O  0 min15% 15% 70%  7 min 15% 15% 70% 15 min 25% 25% 50% 35 min 25% 25% 50% 36min 0% 25% 75% 40 min 0% 60% 40% 45 min 0% 60% 40% 50 min 0% 95% 5% 51min 15% 15% 70% 55 min 15% 15% 70%

[0078] Under these analytical conditions the retention time of thestarting material 1 is 42.7 min and that of the internal standard 44.6min.

[0079] The products 2, 3, 4, 5, 6 and 7 formed were identified bycomparing their retention times with those of the authentic productsprepared by oxidation of compound 1 with 5 equivalents of hydrogenperoxide catalyzed by Mn(TDCPP)Cl in 1:1 dichloromethane/acetonitrilecontaining 0.8 equivalent of hexafluoroisopropanol, 1 equivalent ofammonium acetate and 0.28 equivalent of imidazole. The characteristicsof these products isolated by preparative HPLC on a C18 column are asfollows:

[0080] 2: (This compound was also prepared by oxidation of 1 with 1equivalent of m-chloroperbenzoic acid in dichloromethane):

[0081] HPLC=29.2 min.

[0082]¹H NMR (CDCl₃) δ (ppm) 8.1 (m, 3H), 7.8 (d, 2H), 7.4-7.3 (m, 5H),7.2 (s, 1H), 6.9 (s, 1H), 5.5(d, 1H), 4.6 (t, 1H), 3-9 (q, 1H), 3.2 (m,1H), 3.0(dd, 1H), 2.3 (s, 3H).

[0083] MS (ES⁺) m/z 413 (MH⁺)

[0084] 3:

[0085] HPLC: 30.3 min.

[0086]¹H NMR (CDCl₃) δ (ppm) 8-81 (d, J=3.7 Hz, 2H), 7.93 (d, J=7.5 Hz,1H), 7.80 (d, J=4.6 Hz, 2H), 7.57-7.39 (m, 6H), 7.35 (s, 1H), 7.09 (s,1H), 6.33 (d, J=6.8 Hz, 1H), 5.61 (dd, J=7.6, 1.1 Hz, 1H), 3.56 (dd,J=17.4, 67 Hz, 1H), 3.05 (d, J=17.3 Hz, 1H), 2.37 (s, 3H).

[0087] MS (ES⁺) m/z 413 (MH⁺)

[0088] 4.

[0089] HPLC: 17.7 min.

[0090] H NMR (d₆-DMSO) δ (ppm) 10.0 (d, 1H), 8.8 (d, 2H), 7.9 (d, 2H),7.6-7.4 (m, 6H), 7.2 (s, 1H), 5.5 (d, 1H), 5.3 (t, 1H), 4.5 (m, 3H), 3.9(q, 1H), 3.3 (m, 1H), 3.1 (m, 1H).

[0091] MS (ES⁺) m/z 413 (MH⁺)

[0092] 5:

[0093] HPLC: 26.3 min.

[0094]¹H NMR (CDCl₃) δ (ppm) 8.79 (d, J=5.9 Hz, 2H), 8.02 (d, J=7.5 Hz,1H), 7.79 (dd, J=4.5, 1.4 Hz, 2H), 7.54-7.39 (m, 6H), 7.17 (s, 1H), 5.71(t, J=7.3 Hz, 1H), 5.58 (d, J=7.5 Hz, 1H), 4.81 (dd, J=12.3, 8.1 Hz,1H), 3.84 (dd, J=12.3, 7.0 Hz, 1H), 2.81 (bd s, 1H), 2.39 (s, 3H).

[0095] MS (ES⁺) m/z 413 (MH⁺)

[0096] 6:

[0097] HPLC: 24.9 min.

[0098]¹H NMR (CDCl₃) δ (ppm) 8.79 (d, J=5.9 Hz, 2H), 8.02 (d, J=7.5 Hz,1H), 7.79 (dd, J=4.5, 1.4 Hz, 2H), 7.54-7.39 (m, 6H), 7.17 (s, 1H), 5.71(t, J=77.3 Hz, 1H), 5.58 (d, J=7.5 Hz, 1H), 4.81 (dd, J=12.3, 8.1 Hz,1H), 3.84 (ad, J=12.3, 7.0 Hz, 1H), 2.81 (bd s, 1H), 2.39 (s, 3H).

[0099] MS (ES⁺) m/z 413 (MH⁺)

[0100] 7:

[0101] HPLC: 23.0 min.

[0102]¹H NMR (CDCl₃) δ (ppm) 9.90 (d, 7.9 Hz, 1H), 8.82 (d, J=5.9 Hz,2H), 8.02-7.95 (m, 2H), 7.79 (m, 3H), 7.54-7.41 (m, 5H), 5.65 (d, J=7.6Hz, 1H), 4.72 (m, 1H), 4.12 (dd, J=21.5, 10.2 Hz, 1H), 3.45 (m, 1H),3.27 (dd, J=16.2, 9.7 Hz, 1H).

[0103] MS (ES⁺) m/z 411 (MH⁺)

[0104] The results expressed in terms of areas under the peak withrespect to the internal standard are shown for different solvent systemsin FIG. 1 presented in the Appendix.

[0105] These results make it possible to study the effect of the use ofprotic co-solvents that are good hydrogen-bond donors—such astrifluoroethanol or hexafluoroisopropanol—on the distribution ofproducts. Thus, the presence of trifluoroethanol, or, especially, ofhexafluoroisopropanol, permits decreasing the formation of product 2originating from oxidation of the nitrogen of the pyridine of compound1, in favor of oxidation products 3, 4, 5, 6 and 7. The latter are allthe more interesting since they seem easy to prepare by conventionalsynthesis, in contrast to the N-oxide 2.

EXAMPLE 2

[0106] Oxidation oftrans-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylamine (8) With 1Equivalent of m-Chloroperbenzoic Acid (mCPBA) in Different Solvents:

[0107] To a solution oftrans-2-[4-(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylamine (8) (74mg, 0.2 mmol) in dichloromethane (2 mL) is added, in portions,m-chloroperbenzoic acid (55 mg, 0.22 mmol, 1.1 equiv.). The solution isstirred for 1 hour. After evaporation of the solvent under reducedpressure, the crude product is purified by chromatography on a silicacolumn, eluting with a gradient of 5 to 10% of methanol indichloromethane, to yield 53 mg (69%) of white solid (9).

[0108] To a solution oftrans-2-[4(1,2-diphenyl-1-butenyl)phenoxy]-N,N-dimethylamine (8 (74 mg,0.2 mmol) in hexafluoroisopropanol (2 mL) is added, in portions,m-chloroperbenzoic acid (55 mg, 0.22 mmol, 1.1 equiv.). The solution isstirred for 2 hours. After evaporation of the solvent under reducedpressure, the crude product is purified by chromatography on a silicacolumn, eluting with a gradient of 2 to 10% of methanol indichloromethane, to yield 8 mg of starting material 8 (10%), 7 mg (9%)of 9 and 56 mg (72%) of 10.

[0109]¹H NMR (CDCl₃) δ (ppm) 7.36-7.10 (m, 10H), 6.79 (d, J=8.7 Hz, 2H),6.55 (d, J=8.6 Hz, 2H), 4.42 (t, J=4.0 Hz, 2H), 3.57 (d, J=4.0 Hz, 2H),3.24 (s, 6H), 2.45 (q, J=7.4 Hz, 2H), 0.92 (t, J=7.4 Hz, 3H).

[0110]¹³C NMR (CDCl₃) δ (ppm) 155.6, 143.6, 142.3, 141.8, 138.0, 136.5,132.0, 129.7, 129.5, 128.1, 127.9, 127.2, 126.6, 126.1, 113.4, 70.2,61.9, 59.9, 29.0, 13.5.

[0111] MS (ES⁺) m/z 388 (MH⁺)

[0112]¹H NMR (CDCl₃) δ (ppm) 7.30-7.7.19 (m, 10H), 7.16 (d, J=8.9 Hz,2H), 6.82 (d, J=8.9 Hz, 2H), 4.23 (t, J=-5.1 Hz, 2H), 3.13 (d, J=5.1 Hz,2H), 2.62 (s, 6H), 2.35 (q, J=7.3 Hz, 2H), 0.93 (t, J=7.3 Hz, 3H).

[0113]¹³C NMR (CDCl₃) δ (ppm) 209.8, 156.7, 142.7, 135.1, 131.7, 130.3,128.1, 126.7, 114.0, 72.4, 64.4, 56.8, 44.2, 35.0, 9.8.

[0114] MS (ES⁺) m/z 388 (MH⁺)

[0115] The use of a protic solvent such as hexafluoroisopropanol in theplace of CH₂Cl₂ makes it possible to greatly reduce the formation ofproduct 9, thereby promoting the formation of product 10. The propertiesof this protic solvent, which is a good hydrogen-bond donor, make itpossible, in this case, to limit the N-oxidation of product 8 and topromote the epoxidation of a carbon-carbon double bond.

1. Process of chemoselective oxidation of an organic compound havingseveral oxidizable groups, at least one of which is anitrogen-containing group, said process consisting in: contacting saidorganic compound with a reaction mixture comprising an oxidizing agentand a protic solvent, said protic solvent being capable, in saidreaction medium, of forming a hydrogen bond with one or morenitrogen-containing groups of said organic compound, without leading tocomplete protonation of said nitrogen-containing group or groups, andhence of limiting the oxidation of said nitrogen-containing group orgroups, thus promoting the oxidation of other functional groups of thecompound to be oxidized; and recovering the products resulting from theoxidation reaction.
 2. Process according to claim 1, wherein the proticsolvent is a very weak Brönsted acid.
 3. Process according to claim 2,wherein the protic solvent is characterized by a pK_(a) equal to orgreater than
 9. 4. Process according to one of claims 1 through 3wherein the protic solvent is a good hydrogen-bond donor.
 5. Processaccording to claim 4, wherein the protic solvent is characterized by ahigh α parameter.
 6. Process according to one of claims 1 through 5,wherein the protic solvent is highly polar.
 7. Process according to oneof claims 1 through 6, wherein the protic solvent is weaklynucleophilic.
 8. Process according to claims 1 through 7, wherein theprotic solvent is an alcohol.
 9. Process according to claim 8, whereinthe protic solvent is isopropanol or 2-methylpropanol-2.
 10. Processaccording to claim 8, wherein the protic solvent is a fluorinatedalcohol.
 11. Process according to claim 10, wherein the protic solventis 2-fluoroethanol, 2,2,2-trifluoroethanol,1,1,1,3,3,4,4,4-octafluorobutanol-2,2,2,3,3,4,4,4-heptafluorobutanol-1,2,2,3,3,3-pentafluoropropanol-1,1,1,1,3,3,3-hexafluoro-2-methylpropanol-2or 1,1,1,3,3,3-hexafluoropropanol-2.
 12. Process according to claim 11,wherein the protic solvent is 1,1,1,3,3,3-hexafluoropropanol-2. 13.Process according to one of claims 1 through 12, characterized in thatthe reaction mixture also comprises an inert aprotic solvent. 14.Process according to claim 13, wherein the amount of protic solvent inthe reaction mixture is equal to 1 to 30% volume equivalent with respectto the inert aprotic solvent.
 15. Process according to claim 14, whereinthe amount of protic solvent in the reaction mixture is 10% volumeequivalent with respect to the inert aprotic solvent.
 16. Processaccording to one of claims 1 through 15, wherein the reaction mixturecomprises a catalyst.
 17. Process according to claim 16, wherein thecatalyst is a metalloporphyrin.
 18. Process according to one of claims 1though 17, wherein the protic solvent makes it possible to orient thechemoselectivity of the reaction toward oxidation of carbon-hydrogenbonds or carbon-carbon double bonds.
 19. Process according to claim 18,wherein the protic solvent makes it possible to orient thechemoselectivity of the reaction toward hydroxylation of carbon-hydrogenbonds.
 20. Process according to one of claims 1 through 19,characterized in that the nitrogen-containing group or groups of theorganic compound to be oxidized are selected from primary, secondary ortertiary amines, nitrile, amide or imine groups, or optionallysubstituted aromatic or nonaromatic heterocycles comprising at least onenitrogen atom.
 21. Process according to one of claims 1 through 20,characterized in that the organic compound comprises anitrogen-containing group.